Renal-Clearable Ultrasmall Polypyrrole Nanoparticles with Size-Regulated Property for Second Near-Infrared Light-Mediated Photothermal Therapy

The critical issue that hinders the translation of nanomaterials from basic research to clinical trials is their potential toxicity caused by long-term body retention. It is still a huge challenge to integrate renal-clearable and theranostic properties into one nanomedicine, especially exploring the nanomaterials with optical absorption in the second near-infrared light (NIR II) biowindow with deep penetration and less tissue scattering. Here, ultrasmall polypyrrole (PPy, ≈2 nm)-based theranostic agents via a facile and green one-step method, which exhibit fluorescence (FL)/photoacoustic (PA)/NIR II multimodal imaging, superior photostability, as well as high photothermal conversion efficiency of 33.35% at 808 nm and 41.97% at 1064 nm is developed. Importantly, these ultrasmall PPy-PEG nanoparticles (NPs) reveal abundant tumor accumulation and efficient renal clearance. Both in vitro and in vivo studies indicate that ultrasmall PPy-PEG NPs have excellent photothermal effect under NIR II laser irradiation that can effectively eliminate the tumors with extremely low systemic toxicity.     

Near-Infrared Light Triggered Silk Fibroin Scaffold for Photothermal Therapy and Tissue Repair of Bone Tumors

Silk fibroin (SF) has attracted great interest in bone tissue engineering due to its extraordinary characteristics in terms of mechanical properties, biocompatibility, and biodegradability. SF scaffolds are assembled by biocompatible polydopamine nanoparticles at mesoscopic scale, which endows the scaffolds with a near-infrared (NIR) light response for the treatment of bone tumors. The functionalized SF scaffold not only enhances the significant structure and performance of native SF scaffold for bone treatment and reconstruction, such as primary and mesoscopic structure, multi-level pores, and biodegradation, as well as biocompatibility but also have excellent photothermal effect leading a significant cytotoxicity to MG63 cancer cells after NIR laser irradiation. Moreover, the penetration of NIR light in tissue is improved using an optical fiber, which demonstrates the obtained scaffolds’ great potential in the application of photothermal therapy.     

Intracellular Nanoparticle Formation and Hydroxychloroquine Release for Autophagy-Inhibited Mild-Temperature Photothermal Therapy for Tumors

Mild-temperature photothermal therapy (PTT) of tumors has been intensively explored and adopted in preclinical/clinical trials in recent years. Nevertheless, tumor thermoresistance significantly compromises the therapeutic efficacy of mild-temperature PTT, and therefore, the extra addition of anti-thermoresistance agent is needed. Herein, by rational design of a peptide-hydroxychloroquine (HCQ) conjugate Cypate-Phe-Phe-Lys(SA-HCQ)-Tyr(H₂PO₃)-OH (Cyp-HCQ-Yp), a “smart” strategy of enzyme-triggered simultaneously intracellular photothermal nanoparticle formation and HCQ release is proposed for autophagy-inhibited mild-temperature PTT of tumor. In vitro results show that, under sequential catalysis of enzymes alkaline phosphatase and carboxylesterase, Cyp-HCQ-Yp is converted to Cypate-Phe-Phe-Lys(SA)-Tyr-OH (Cyp-Y) which self-assembles into its nanoparticle Cyp-NP and HCQ is released from Cyp-HCQ-Yp. By comparing with two control agents, it is validated that the exceptional therapeutic effect of Cyp-HCQ-Yp on tumor in vivo is achieved by its dual-enzyme-controlled intracellular nanoparticle formation and autophagy inhibition in tumors.     

Nanoagent-Promoted Mild-Temperature Photothermal Therapy for Cancer Treatment

Photothermal therapy (PTT), which utilizes near-infrared light-absorbing agents to ablate tumor, has emerged as a highly promising anticancer strategy and received intensive clinical trials in recent years. Mild-temperature PTT, which circumvents the limitations of conventional PTT (e.g., thermoresistance and adverse effects), is emerging and shows great potential in the forthcoming clinical applications. However, mild-temperature PTT without adjuvant therapy is not able to completely eradicate tumors because its therapeutic efficacy is dramatically impaired by its inferior heat intensity. As a result, strategies capable of enhancing the anticancer efficacy of mild-temperature PTT are urgently necessitated, which mainly rely on on-demand fabrication of functionalized nanoagents. In this review, the strategies of nanoagent-promoted mild-temperature PTT are highlighted. Furthermore, challenges and opportunities in this field are rationally proposed, and hopefully people can be encouraged by this promising anticancer therapy.     

Effective Eradication of Tumors by Enhancing Photoacoustic-Imaging-Guided Combined Photothermal Therapy and Ultrasonic Therapy

Exploiting a comprehensive strategy that processes diagnosis and therapeutic functions is desired for eradicating tumors. In this study, two versatile nanoparticles are introduced: one is polyethylene glycol- and polyethyleneimine-modified gold nanorods (mPEG–PEI–AuNRs), and the other is formed by electrostatic interactions between mPEG–PEI and calcium carbonate nanoparticles (mPEG–PEI/CaNPs). These two nanoparticles possess following favorable properties: 1) mPEG–PEI–AuNRs and mPEG–PEI/CaNPs show not only high cell uptake in acidic tumoral pH, but also efficient accumulation in tumors with prolonged circulation. 2) mPEG–PEI/CaNPs can generate carbon dioxide (CO₂) bubbles in acidic tumoral environment and the photoacoustic (PA) signals from mPEG–PEI–AuNRs can be enhanced with the generation of CO₂ bubbles. 3) The tumors can be eradicated by combining photothermal therapy (PTT) with ultrasonic therapy (UST) under the near-infrared (NIR) laser and ultrasonic irradiation with the presence of mPEG–PEI–AuNRs and CO₂ bubbles from mPEG–PEI/CaNPs. The detailed evaluation of cellular uptake, photothermal property of mPEG–PEI–AuNRs, CO₂ bubbles’ generation from mPEG–PEI/CaNPs, imaging, and combined PTT and UST are carried out in vitro or in vivo. This work has great potential usage for diagnosis and treatment in the future.     

Injectable In Situ Induced Robust Hydrogel for Photothermal Therapy and Bone Fracture Repair

Malignant bone tumors are often accompanied by osteolytic destruction and severe pathological fractures. Current therapeutic strategies can largely inhibit tumor proliferation, but the high recurrence rate of tumors and related bone defects remain a significant challenge. This study aims to address these issues by developing a novel near-infrared (NIR) light-responsive and a mechanically strong hydrogel that offers excellent photothermal tumor therapy and bone fracture repair capabilities. The as-prepared hydrogel exhibits good biocompatibility and an ultra-strong photothermal effect due to the formation of a complex network with up-conversion lanthanide-Au hybrid nanoparticles and alginate molecules. A subcutaneous tumor model is used to demonstrate that tumors can be efficiently eradicated via local photothermal treatment, where there is no tumor recurrence within the observation period. Moreover, the injected hydrogel becomes mechanically strong due to in situ Ca²⁺ crosslinking, which provides a supportive matrix to promote the repair of bone defects via stabilization of the fractured bone structure. The high photothermal effect and robust support offered by this single material demonstrate the potential of using the proposed hydrogel for the simultaneous treatment of bone tumor removal and bone healing.     

Near‐Infrared Light‐Absorptive Stealth Liposomes for Localized Photothermal Ablation of Tumors Combined with Chemotherapy

Although near‐infrared (NIR) light‐absorbing organic dyes have recently been proposed for photothermal ablation of tumors, their clinical applications have often been hampered by problems such as low water solubility and minimal tissue absorption. Rapid development of nanotechnology provides various novel nanostructures to address these issues. In this work, doxorubicin (DOX)‐loaded stealth liposomes are engineered through the incorporation of an NIR‐absorptive heptamethine indocyanine dye IR825 into the thermoresponsive liposomes for photothermal/chemo combined cancer therapy. It is demonstrated that the lipid nanostructure can enhance the bioavailability of water‐insoluble IR825 for efficient photothermal treatment, while delivering the anticancer drug doxorubicin to achieve simultaneous anticancer medication. The combined treatment of photothermal ablation and chemotherapy synergistically improves the overall cancer cell killing efficiency, which can be of future clinical interest.     

NIR-II Responsive Inorganic 2D Nanomaterials for Cancer Photothermal Therapy: Recent Advances and Future Challenges

Non-invasive cancer photothermal therapy (PTT) is a promising replacement for traditional cancer treatments. The second near-infrared region induced PTT (NIR-II PTT, 1000–1500 nm) with less energy dissipation has been developed for deeper-seated tumor treatment in recent years compared with the traditional first near-infrared light (750–1000 nm). In addition, the use of emerging inorganic 2D nanomaterials as photothermal agents (PTAs) further enhanced PTT efficiency due to their intrinsic photothermal properties. NIR-II light stimulated inorganic 2D nanomaterials for PTT is becoming a hot topic in both academic and clinical fields. This review summarizes the categories, structures, and photothermal conversion properties of inorganic 2D nanomaterials for the first time. The recent synergistic strategies of NIR-II responsive PTT combined with other treatment approaches including chemotherapy, chemodynamic therapy, photodynamic therapy, radiotherapy are summarized. The future challenges and perspectives on these 2D nanomaterials for NIR-II responsive PTT systems construction are further discussed.     

Renal-Clearable Nickel-Doped Carbon Dots with Boosted Photothermal Conversion Efficiency for Multimodal Imaging-Guided Cancer Therapy in the Second Near-Infrared Biowindow

Photothermal agents with absorption in the second near-infrared (NIR-II) biowindow have attracted increasing attention for photothermal therapy (PTT) on account of their deeper tissue penetration capacity. However, most of the current NIR-II photothermal agents exhibit low photothermal conversion efficiency (PCE) and long-term biotoxicity. To overcome these shortcomings, herein, nickel and nitrogen co-doped carbon dots (Ni-CDs, ≈4.6 nm) are prepared via a facile one-pot hydrothermal approach for imaging-guided PTT in the NIR-II window. The Ni-CDs exhibit significant absorption in the NIR-II region with a distinguished PCE as high as 76.1% (1064 nm) and have excellent photostability and biocompatibility. Furthermore, the Ni-CDs can be employed as photothermal, photoacoustic, and magnetic resonance imaging contrast agents because of their outstanding photothermal effect and instinctive paramagnetic feature. The Ni-CDs demonstrate significant PTT efficacy of tumor upon 1064 nm irradiation with a low power density (0.5 W cm⁻²). The Ni-CDs can be eliminated from the body via a renal filtration pathway, thereby minimizing their long-term biotoxicity. Therefore, this work provides a simple and feasible approach to develop photothermal agents with remarkable PCE in the NIR-II region, presenting good biosafety for multimodal imaging-guided PTT of tumor.     

Organic Semiconducting Macromolecular Dyes for NIR-II Photoacoustic Imaging and Photothermal Therapy

Owing to the unique advantages of photoacoustic imaging (PAI) and photothermal therapy (PTT) conducted over the near-infrared-II (NIR-II) window, the development of high-efficiency optical agents with NIR-II light responsiveness is of great significance. Despite the diversity of optical agents developed for NIR-II PAI and PTT, most of them are based on inorganic nanomaterials and small molecular dyes, whose biosafety and photostability need to be further assessed, respectively. Organic semiconducting macromolecular dyes (OSMDs) featuring a large semiconducting backbone are becoming alternative candidates for NIR-II PAI and PTT owing to their reliable biocompatibility, durable photostability, and ideal photothermal conversion capability. This paper reviews the current progress of OSMD-based PAI and PTT in the NIR-II optical window. The three main types of OSMDs with different skeleton architectures are introduced, and their applications for NIR-II PAI (tumor imaging, stem cell tracking, and vasculature imaging) and PTT (tumor ablation) are described. Viable strategies for further improving the NIR-II PAI performance of OSMDs are discussed. Finally, some major issues faced by OSMDs in NIR-II PAI and PTT are raised, and the future development directions of OSMDs are analyzed.     

Tumor Microenvironment Activated Photothermal Strategy for Precisely Controlled Ablation of Solid Tumors upon NIR Irradiation

Photothermal ablation has provided emerging and promising opportunities to further potentiate the efficacy of postoperative chemotherapy of tumor. However, it still cannot achieve a high level of selectivity because extraneous photodamage along the optical path to the tumor is unavoidable as the result of the uncontrollable distribution of the photothermal agents. In addition, it is technically difficult to keep photoirradiation localizing only on cancer cells. In this report, a new strategy is introduced for precisely controlled ablation of tumor through tumor microenvironment activated near‐infrared (NIR) photothermal therapy. By taking advantage of the pH‐dependent light‐heat conversion property of Au@PANI nanoparticles, much higher photothermal effect at pH 6.5 than that at pH 7.4 is achieved. Therefore, in normal tissues and blood vessels, NIR irradiation cannot lead to a lethal temperature with little or no harm to normal cells. In contrast, in acidic tumor microenvironment, the photothermal effect is activated. Consequently, NIR irradiation can effectively kill cancer cells through local hyperthermia. Importantly, with the benefit of the internal and external control to switch on the photothermal ablation, the technical difficulty to precisely localize laser irradiation on tumor cells can be circumvented.     

Charge-Driven Self-Assembled Microspheres Hydrogel Scaffolds for Combined Drug Delivery and Photothermal Therapy of Diabetic Wounds

The treatment of diabetic wound remains a big clinical challenge. Hydrogel that can provide physical barrier and humidity displays amazing potentials for managing the diabetic wounds healing. Herein, a new charge-driven self-assembled microsphere hydrogel scaffold (SMHS) is reported based on an electric charge interaction, by combining use of black phosphorus (BP)-contained chitosan methacryloyl (CS) microspheres with positive charge and basic fibroblast growth factor-contained hyaluronic acid methacryloyl (HA) microspheres with negative charge. The weak charge attraction among microspheres gives the SMHS the injectable characteristic. Due to the existence of BP, near-infrared (NIR) irradiation has obvious effects on the degradation and drug release behaviors of SMHS. Significantly, SMHS that combines the short-term physical (photothermal) intervention and long-term chemical (drug release) intervention may be promising in spatio-temporal regulation of regenerative microenvironment. SMHS with NIR irradiation (SMHS+NIR) can promote cell proliferation, cell migration, angiogenesis and macrophage polarization. Moreover, in diabetic rat skin wounds, SMHS+NIR significantly accelerates the wound healing process by simultaneously inhibiting the inflammatory response, promoting angiogenesis and tissues remodeling. The outcome of this research not only provides a biomaterial for diabetic wounds healing, but also demonstrates a new strategy for designing novel hydrogel-based biomaterials which have the free editing and combination functions.     

Recent Advances and Clinical Potential of Near Infrared Photothermal Conversion Materials for Photothermal Hepatocellular Carcinoma Therapy

Growing concern about photothermal tumor therapy (PTT) as a promising alternative to conventional liver cancer treatment, which is a treatment strategy that utilizes near-infrared (NIR) light-induced photothermal agents (PTAs) to yield photothermal effects to localize thermal damage for tumors. Herein, given the gap between experimental research and clinical application, this review seeks to timely summarize and highlight the recent progress of PTAs used for photothermal treatment of liver cancer in vivo and in vitro in the last five-year. The implications of various PTAs on the multifunctional photothermal conversion capability, the structure-performance correlations of PTT, together with the evaluation of their potential in application are systematically dissected to further dig out what the buried mechanism is. Besides, higher requirements are put forward for the discrepancies and crucial issues faced by different PTAs in PTT with related medical technical obstacles being conquered, which lays a solid theoretical foundation for the medical field of oncology treatment as a whole, especially liver cancer. Finally, it is expected that this review can present valuable guidance for the design of efficient, photostability, and biosafety-aware PTAs for anticancer therapy while stepping into the fast traffic lane for the conversion from bench to bedside in the foreseeable future.     

Light‐Triggered Clustered Vesicles with Self‐Supplied Oxygen and Tissue Penetrability for Photodynamic Therapy against Hypoxic Tumor

Smart nanocarriers are of particular interest for highly effective photodynamic therapy (PDT) in the field of precision nanomedicine. Nevertheless, a critical challenge still remains in the exploration of potent PDT treatment against hypoxic tumor. Herein, light‐triggered clustered polymeric vesicles for photoinduced hypoxic tumor ablation are demonstrated, which are able to deeply penetrate into the tumor and simultaneously afford oxygen supply upon light irradiation. Hydrogen peroxide (H₂O₂) and poly(amidoamine) dendrimer conjugating chlorin e6/cypate (CC‐PAMAM) are coassembled with reactive‐oxygen‐species‐responsive triblock copolymer into the polymeric vesicles. Upon 805 nm irradiation, the vesicles exhibit the light‐triggered thermal effect that is able to decompose H₂O₂ into O₂, which distinctly ensures the alleviation of tumor hypoxia at tumor. Followed by 660 nm irradiation, the vesicles are rapidly destabilized through singlet oxygen‐mediated cleavage of copolymer under light irradiation and thus allow the release of photoactive CC‐PAMAM from the vesicular chambers, followed by their deep penetration in the poorly permeable tumor. Consequently, the light‐triggered vesicles with both self‐supplied oxygen and deep tissue penetrability achieve the total ablation of hypoxic hypopermeable pancreatic tumor through photodynamic damage. These findings represent a general and smart nanoplatform for effective photoinduced treatment against hypoxic tumor.     

Design and Synthesis of “All‐in‐One” Multifunctional FeS2 Nanoparticles for Magnetic Resonance and Near‐Infrared Imaging Guided Photothermal Therapy of Tumors

The ideal theranostic nanoplatform for tumors is a single nanoparticle that has a single semiconductor or metal component and contains all multimodel imaging and therapy abilities. The design and preparation of such a nanoparticle remains a serious challenge. Here, with FeS₂ as a model of a semiconductor, the tuning of vacancy concentrations for obtaining “all‐in‐one” type FeS₂ nanoparticles is reported. FeS₂ nanoparticles with size of ≈30 nm have decreased photoabsorption intensity from the visible to near‐infrared (NIR) region, due to a low S vacancy concentration. By tuning their shape/size and then enhancing the S vacancy concentration, the photoabsorption intensity of FeS₂ nanoparticles with size of ≈350 nm (FeS₂‐350) goes up with the increase of the wavelength from 550 to 950 nm, conferring the high NIR photothermal effect for thermal imaging. Furthermore, this nanoparticle has excellent magnetic properties for T₂‐weighted magnetic resonance imaging (MRI). Subsequently, FeS₂‐350 phosphate buffer saline (PBS) dispersion is injected into the tumor‐bearing mice. Under the irradiation of 915‐nm laser, the tumor can be ablated and the metastasis lesions in liver suffer significant inhibition. Therefore, FeS₂‐350 has great potential to be used as novel “all‐in‐one” multifunctional theranostic nanoagents for MRI and NIR dual‐modal imaging guided NIR‐photothermal ablation therapy (PAT) of tumors.     

An Injectable Hydrogel for Simultaneous Photothermal Therapy and Photodynamic Therapy with Ultrahigh Efficiency Based on Carbon Dots and Modified Cellulose Nanocrystals

The convenience of injectable hydrogels that can provide high loading of diverse phototherapy agents and further long-time retention at the tumor site has attracted tremendous interest in simultaneous photothermal and photodynamic cancer therapies. However, to incorporate the phototherapy agents into hydrogels, complex modifications are generally unavoidable. Moreover, these phototherapy agents usually suffer from low efficiency and work at different irradiation wavelengths outside the near infrared windows. Hence, a method for the fabrication of an injectable hydrogel for simultaneous photothermal therapy and photodynamic therapy, through the Schiff-base reaction between amido modified carbon dots (NCDs) and aldehyde modified cellulose nanocrystals is proposed. The NCDs act as both phototherapy agents and crosslinkers to form hydrogels. Significantly, the NCDs demonstrate an extremely high photothermal conversion efficiency of 77.6% which is among the highest levels for photothermal agents and a high singlet quantum yield of 0.37 under a single 660 nm light-emitting diode irradiation. The hydrogels are examined through in vitro and in vivo animal experiments which show nontoxic and effectively tumor inhibition. Thus, the strategy of direct reaction of phototherapy agents and the matrix not only provides new strategies for injectable hydrogel fabrication but paves a new road for advanced tumor treatment.     

Engineering of Multifunctional Nano‐Micelles for Combined Photothermal and Photodynamic Therapy Under the Guidance of Multimodal Imaging

The integration of diagnostic and therapeutic functionalities on a single theranostic nano‐system holds great promise to enhance the accuracy of diagnosis and improve the efficacy of therapy. Herein, a multifunctional polymeric nano‐micelle system that contains a photosensitizer chlorin e6 (Ce6) is successfully fabricated, at the same time serving as a chelating agent for Gd³⁺, together with a near‐infrared (NIR) dye, IR825. With a r₁ relativity 7 times higher than that of the commercial agent Magnevist, strong fluorescence offered by Ce6, and high NIR absorbance attributed to IR825, these theranostic micelles can be utilized as a contrast agent for triple modal magnetic resonance (MR), fluorescence, and photoacoustic imaging of tumors in a mouse model. The combined photothermal and photodynamic therapy is then carried out, achieving a synergistic anti‐tumor effect both in vitro and in vivo. Different from single photo treatment modalities which only affect the superficial region of the tumor under mild doses, the combination therapy at the same dose using this agent is able to induce significant damage to both superficial and deep parts of the tumor. Therefore, this work presents a polymer based theranostic platform with great potential in multimodal imaging and combination therapy of cancer.     

Controlled Growth of Hierarchical Bi2Se3/CdSe-Au Nanorods with Optimized Photothermal Conversion and Demonstrations in Photothermal Therapy

Integrating multiple mechanisms to maximize photothermal conversion efficiency is a significant strategy but remains challenging to construct therapeutic agents toward photothermal tumor treatment. Here, an approach to synthesize asymmetric Bi₂Se₃/CdSe-Au hierarchical nanorods with excellent photothermal conversion is reported. Ag wetting-layer is firstly grown to help overcome the interfacial lattice mismatch and promote the site-selective growth of AgCdSe onto one end or side surface of Au nanorods. Subsequently, extraction of Ag⁺ ions out of lattice is observed during cation exchange reaction and epitaxial growth of Bi₂Se₃ shell. Bi₂Se₃/CdSe heterojunction with type-II band alignment is formed and located at the plasmonic hotspots of Au nanorods, which experiences enhanced light absorption and accelerates the charge separation of photo-excited carriers. Under excitation of near-infrared 808 nm laser, the matchstick-like Bi₂Se₃/CdSe-Au nanorods show an excellent photothermal conversion, with 4.3 times temperature increment ( Δ T) than that of bare Au nanorods. Moreover, in vitro and in vivo experiments verify them as excellent photothermal therapeutic agents.     

Three-Step Regenerative Strategy: Multifunctional Bilayer Hydrogel for Combined Photothermal/Photodynamic Therapy to Promote Drug-Resistant Bacteria-Infected Wound Healing

The drug-resistant bacterial-infected skin wound is still a severe healthcare problem. Uncontrolled bacterial infection, abundant reactive oxygen species (ROS) content, and prolonged inflammatory response are detrimental to wound healing. Moreover, excessive vessel growth can result in unsatisfactory scar formation. Herein, a three-step regenerative strategy based on a bilayered gelatin/acryloyl β-cyclodextrin (BGACD) hydrogel containing physical host–guest complexations and chemical crosslinks is proposed. The hydrogel is loaded with humic acids (HAs) and astragaloside IV (AS) in the lower layer and verteporfin (Vt) in the upper layer. Different gelatin/acryloyl β-cyclodextrin ratios endow the lower and upper layers of the hydrogel with different degradation rates. Under light irradiation, the combination of HAs-induced photothermal therapy (PTT) and verteporfin-induced photodynamic therapy effectively inhibits MRSA growth. The HAs and astragaloside IV are released from the lower layer to scavenge ROS and promote M2 macrophage polarization and angiogenesis during the inflammation and early proliferation phases, while verteporfin releases from the upper layer suppress excessive vessel growth during the late proliferation and remodeling phases. The HAs-AS@Vt@BGACD hydrogel successfully achieves rapid and scarless wound healing in an MRSA-infected wound model in rats. Therefore, the HAs-AS@Vt@BGACD hydrogel shows promising potential for the treatment of drug-resistant bacteria-infected skin wound healing.     

Ultrasmall Semiconducting Polymer Dots with Rapid Clearance for Second Near‐Infrared Photoacoustic Imaging and Photothermal Cancer Therapy

Phototheranostic agents in the second near‐infrared (NIR‐II) window (1000–1700 nm) are emerging as a promising theranostic platform for precision medicine due to enhanced penetration depth and minimized tissue exposure. The development of metabolizable NIR‐II nanoagents for imaging‐guided therapy are essential for noninvasive disease diagnosis and precise ablation of tumors. Herein, metabolizable highly absorbing NIR‐II conjugated polymer dots (Pdots) are reported for the first time for photoacoustic imaging guided photothermal therapy (PTT). The unique design of low‐bandgap D‐A π‐conjugated polymer (DPP‐BTzTD) together with modified nanoreprecipitation conditions allows to fabricate NIR‐II absorbing Pdots with ultrasmall (4 nm) particle size. Extensive experimental tests demonstrate that the constructed Pdots exhibit good biocompatibility, excellent photostability, bright photoacoustic signals, and high photothermal conversion efficiency (53%). In addition, upon tail‐vein intravenous injection of tumor‐bearing mice, Pdots also show high‐efficient tumor ablation capability with rapid excretion from the body. In particular, both in vitro and in vivo assays indicate that the Pdots possess remarkable PTT performance under irradiation with a 1064 nm laser with 0.5 W cm^?2, which is much lower than its maximum permissible exposure limit of 1 W cm^?2. This pilot study thus paves a novel avenue for the development of organic semiconducting nanoagents for future clinical translation.